The American Cancer Society announces annually the staggering number of women that are diagnosed with and die from invasive breast cancer in the United States. As with all cancers, treatment success rates are higher in early stages and treatment options vary with disease progression. Despite considerable focus on curing or ameliorating this disease, there are still critical gaps in our knowledge base that hinder the development of more effective forms of treatment for later-stage cancer. Importantly, several studies have also shown that older women are less likely to choose surgery or radiation, decreasing their survival rates significantly (Archives of Surgery, October 2006). Destruction of breast cancer cells by monoclonal antibodies that bind to specific targets on their surface shows great promise as a new treatment modality. However, it has become apparent that targets unique to the surface of tumor cells may be limited. The Major Histocompatability Complex (MHC) class I system can be thought of as nature's proteomic scanning chip because it continuously processes intracellular protein and presents peptides on the surface of cells. From recent studies, we show unique expression of peptide-MHC class I targets on the surface of cancer cells compared to normal cells. These tumor-specific peptide-MHC complexes represent targets for antibody binding however, antibodies that have recognition specificity for peptide-MHC complexes are not common. We have developed technology to generate antibodies that mimic the binding specificity of T cell receptors (TCR) designated as TCRm. We have identified a TCRm that can bind to and mediate tumor cell death in vitro and cause tumor shrinkage in vivo. In this Phase I study, we will extend our earlier observations by fully characterizing the murine 3.2G1TCRm's anti-tumor properties in a xenograft mouse model. We will determine the expression frequency for hCG ( antigen and the GVL peptide-HLA-A2 epitope. We will then determine the therapeutic effectiveness and the relationship between target density and TCRm- mediated tumor shrinkage. The Specific Aims are: 1) to establish the frequency of hCG antigen and the GVL peptide-HLA-A2 epitope in breast cancer cells and 2) to determine the generality of anti-tumor activity mediated by the 3.2G1 TCRm. We expect that the results from this study will lead to the development of TCRms as a novel class of agents for cancer treatment. Moreover, these studies are expected to validate the GVL peptide HLA-A2 epitope for cancer immunotherapy. Finally, the results from this study will be used to submit an STTR phase II application to carry out the pre-clinical development of the chimeric and/or humanized 3.2G1 TCRm as a novel treatment modality for breast cancer. PUBLIC HEALTH RELEVANCE: The American Cancer Society announces annually the staggering number of women that are diagnosed with and die from invasive breast cancer in the United States. Importantly, studies have shown that older women are less likely to choose traditional therapies, decreasing their survival rates significantly. As such, new treatment modalities are necessary to reduce the death and suffering from breast cancer. This proposal aims to examine the anti-tumor properties of a new class of antibodies that recognize novel targets on breast carcinoma cells. Completion of these studies is expected to lead to development of new therapeutic antibodies for the treatment of breast cancer.